Infantile hypercalcaemia type 1: A vitamin D-mediated, under-recognised cause of hypercalcaemia

A 33-year-old gentleman of Egyptian heritage presented with a 21 years history of unexplained and recurrent hypercalcaemia, nephrolithiasis, nephrocalcinosis, and myocarditis. A similar history was also found in two first-degree relatives. Further investigation into the vitamin D metabolism pathway identified the biochemical hallmarks of infantile hypercalcaemia type 1 (IIH). A homozygous, likely pathogenic, variant in CYP24A1 was found on molecular genetic analysis confirming the diagnosis. Management now focuses on removing excess vitamin D from the metabolic pathway as well as reducing calcium intake to achieve serum-adjusted calcium to the middle of the reference range. If undiagnosed, IIH can cause serious renal complications and metabolic bone disease

Incidental detection of classical galactosemia through newborn screening for phenylketonuria: a 10-year retrospective audit to determine the efficacy of this approach

In the UK, Classical Galactosaemia (CG) is identified incidentally from the Newborn Screening (NBS) for phenylketonuria (PKU) using an “Other disorder suspected” (ODS) pathway when phenylalanine (Phe) and tyrosine (Tyr) concentrations are increased. We aimed to determine the efficacy of CG detection via NBS and estimate the incidence of CG in live births in the UK. A survey was sent to all UK NBS laboratories to collate CG cases diagnosed in the UK from 2010 to 2020. Cases of CG diagnosed were determined if detected clinically, NBS, or by family screening, as well as age at diagnosis. Cases referred via the ODS pathway were also collated, including the final diagnosis made. Responses were obtained from 13/16 laboratories. Between 2010 and 2020, a total of 6,642,787 babies were screened, and 172 cases of CG were identified. It should be noted that 85/172 presented clinically, 52/172 were identified by NBS, and 17/172 came from family screening. A total of 117 referrals were made via the ODS pathway, and 45/117 were subsequently diagnosed with CG. Median (interquartile range) age at diagnosis by NBS and clinically was 8 days (7–11) and 10 days (7–16), respectively (Mann–Whitney U test, U = 836.5, p-value = 0.082). The incidence of CG is 1:38,621 live births. The incidence of CG in the UK is comparable with that of other European/western countries. No statistical difference was seen in the timing of diagnosis between NBS and clinical presentation based on the current practice of sampling on day 5. Bringing forward the day of NBS sampling to day 3 would increase the proportion diagnosed with CG by NBS from 52/172 (30.2%) to 66/172 (38.4%)

Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer

A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency. Using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but its drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RARα and treats APL in cell and animal models and human patients. ATRA-induced Pin1 ablation also inhibits triple negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors

Incidental Detection of Classical Galactosemia through Newborn Screening for Phenylketonuria: A 10-Year Retrospective Audit to Determine the Efficacy of This Approach

Peer reviewed: TruePublication status: PublishedIn the UK, Classical Galactosaemia (CG) is identified incidentally from the Newborn Screening (NBS) for phenylketonuria (PKU) using an “Other disorder suspected” (ODS) pathway when phenylalanine (Phe) and tyrosine (Tyr) concentrations are increased. We aimed to determine the efficacy of CG detection via NBS and estimate the incidence of CG in live births in the UK. A survey was sent to all UK NBS laboratories to collate CG cases diagnosed in the UK from 2010 to 2020. Cases of CG diagnosed were determined if detected clinically, NBS, or by family screening, as well as age at diagnosis. Cases referred via the ODS pathway were also collated, including the final diagnosis made. Responses were obtained from 13/16 laboratories. Between 2010 and 2020, a total of 6,642,787 babies were screened, and 172 cases of CG were identified. It should be noted that 85/172 presented clinically, 52/172 were identified by NBS, and 17/172 came from family screening. A total of 117 referrals were made via the ODS pathway, and 45/117 were subsequently diagnosed with CG. Median (interquartile range) age at diagnosis by NBS and clinically was 8 days (7–11) and 10 days (7–16), respectively (Mann–Whitney U test, U = 836.5, p-value = 0.082). The incidence of CG is 1:38,621 live births. The incidence of CG in the UK is comparable with that of other European/western countries. No statistical difference was seen in the timing of diagnosis between NBS and clinical presentation based on the current practice of sampling on day 5. Bringing forward the day of NBS sampling to day 3 would increase the proportion diagnosed with CG by NBS from 52/172 (30.2%) to 66/172 (38.4%)

Pan-cancer proteogenomics connects oncogenic drivers to functional states

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types

Open Letter to The American Association for the Advancement of Science

This is an open letter concerning the recent launch of the new open access journal, Science Advances. In addition to the welcome diversification in journal choices for authors looking for open access venues, there are many positive aspects of Science Advances: its broad STEM scope, its interest in cross-disciplinary research, and the offering of fee waivers. While we welcome the commitment of the Association to open access, we are also deeply concerned with the specific approach. Herein, we outline a number of suggestions that are in line with both the current direction that scholarly publishing is taking and the needs expressed by the open access community, which this journal aims to serve